National Institute of Allergy and Infectious Diseases
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Research output, citation impact, and the most-cited recent papers from National Institute of Allergy and Infectious Diseases (United States). Aggregated across the NobleBlocks index of 300M+ scholarly works.
Top-cited papers from National Institute of Allergy and Infectious Diseases
Studies of the human microbiome have revealed that even healthy individuals differ remarkably in the microbes that occupy habitats such as the gut, skin and vagina. Much of this diversity remains unexplained, although diet, environment, host genetics and early microbial exposure have all been implicated. Accordingly, to characterize the ecology of human-associated microbial communities, the Human Microbiome Project has analysed the largest cohort and set of distinct, clinically relevant body habitats so far. We found the diversity and abundance of each habitat’s signature microbes to vary widely even among healthy subjects, with strong niche specialization both within and among individuals. The project encountered an estimated 81–99% of the genera, enzyme families and community configurations occupied by the healthy Western microbiome. Metagenomic carriage of metabolic pathways was stable among individuals despite variation in community structure, and ethnic/racial background proved to be one of the strongest associations of both pathways and microbes with clinical metadata. These results thus delineate the range of structural and functional configurations normal in the microbial communities of a healthy population, enabling future characterization of the epidemiology, ecology and translational applications of the human microbiome. The Human Microbiome Project Consortium reports the first results of their analysis of microbial communities from distinct, clinically relevant body habitats in a human cohort; the insights into the microbial communities of a healthy population lay foundations for future exploration of the epidemiology, ecology and translational applications of the human microbiome. The Human Microbiome Project (HMP), supported by the National Institutes of Health Common Fund, has the goal of characterizing the microbial communities that inhabit and interact with the human body in sickness and in health. In two Articles in this issue of Nature, the HMP Consortium presents the first population-scale details of the organismal and functional composition of the microbiota across five areas of the body. An associated News & Views discusses the initial results — which, along with those of a series of co-publications, already constitute the most extensive catalogue of organisms and genes related to the human microbiome yet published — and highlights some of the major questions that the project will tackle in the next few years.
Most intracellular parasites employ sophisticated mechanisms to direct biogenesis of a vacuolar replicative niche that circumvents default maturation through the endolysosomal cascade. However, this is not the case of the Q fever bacterium, Coxiella burnetii. This hardy, obligate intracellular pathogen has evolved to not only survive, but to thrive, in the harshest of intracellular compartments: the phagolysosome. Following internalization, the nascent Coxiella phagosome ultimately develops into a large and spacious parasitophorous vacuole (PV) that acquires lysosomal characteristics such as acidic pH, acid hydrolases and cationic peptides, defences designed to rid the host of intruders. However, transit of Coxiella to this environment is initially stalled, a process that is apparently modulated by interactions with the autophagic pathway. Coxiella actively participates in biogenesis of its PV by synthesizing proteins that mediate phagosome stalling, autophagic interactions, and development and maintenance of the mature vacuole. Among the potential mechanisms mediating these processes is deployment of a type IV secretion system to deliver effector proteins to the host cytosol. Here we summarize our current understanding of the cellular events that occur during parasitism of host cells by Coxiella.
Aerosol and Surface Stability of SARS-CoV-2 In this research letter, investigators report on the stability of SARS-CoV-2 and SARS-CoV-1 under experimental conditions. The viability of the two virus...
The outbreak of a novel coronavirus (2019-nCoV) represents a pandemic threat that has been declared a public health emergency of international concern. The CoV spike (S) glycoprotein is a key target for vaccines, therapeutic antibodies, and diagnostics. To facilitate medical countermeasure development, we determined a 3.5-angstrom-resolution cryo-electron microscopy structure of the 2019-nCoV S trimer in the prefusion conformation. The predominant state of the trimer has one of the three receptor-binding domains (RBDs) rotated up in a receptor-accessible conformation. We also provide biophysical and structural evidence that the 2019-nCoV S protein binds angiotensin-converting enzyme 2 (ACE2) with higher affinity than does severe acute respiratory syndrome (SARS)-CoV S. Additionally, we tested several published SARS-CoV RBD-specific monoclonal antibodies and found that they do not have appreciable binding to 2019-nCoV S, suggesting that antibody cross-reactivity may be limited between the two RBDs. The structure of 2019-nCoV S should enable the rapid development and evaluation of medical countermeasures to address the ongoing public health crisis.
BACKGROUND: Functional annotation of differentially expressed genes is a necessary and critical step in the analysis of microarray data. The distributed nature of biological knowledge frequently requires researchers to navigate through numerous web-accessible databases gathering information one gene at a time. A more judicious approach is to provide query-based access to an integrated database that disseminates biologically rich information across large datasets and displays graphic summaries of functional information. RESULTS: Database for Annotation, Visualization, and Integrated Discovery (DAVID; http://www.david.niaid.nih.gov) addresses this need via four web-based analysis modules: 1) Annotation Tool - rapidly appends descriptive data from several public databases to lists of genes; 2) GoCharts - assigns genes to Gene Ontology functional categories based on user selected classifications and term specificity level; 3) KeggCharts - assigns genes to KEGG metabolic processes and enables users to view genes in the context of biochemical pathway maps; and 4) DomainCharts - groups genes according to PFAM conserved protein domains. CONCLUSIONS: Analysis results and graphical displays remain dynamically linked to primary data and external data repositories, thereby furnishing in-depth as well as broad-based data coverage. The functionality provided by DAVID accelerates the analysis of genome-scale datasets by facilitating the transition from data collection to biological meaning.
BACKGROUND: Although several therapeutic agents have been evaluated for the treatment of coronavirus disease 2019 (Covid-19), no antiviral agents have yet been shown to be efficacious. METHODS: We conducted a double-blind, randomized, placebo-controlled trial of intravenous remdesivir in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection. Patients were randomly assigned to receive either remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) or placebo for up to 10 days. The primary outcome was the time to recovery, defined by either discharge from the hospital or hospitalization for infection-control purposes only. RESULTS: A total of 1062 patients underwent randomization (with 541 assigned to remdesivir and 521 to placebo). Those who received remdesivir had a median recovery time of 10 days (95% confidence interval [CI], 9 to 11), as compared with 15 days (95% CI, 13 to 18) among those who received placebo (rate ratio for recovery, 1.29; 95% CI, 1.12 to 1.49; P<0.001, by a log-rank test). In an analysis that used a proportional-odds model with an eight-category ordinal scale, the patients who received remdesivir were found to be more likely than those who received placebo to have clinical improvement at day 15 (odds ratio, 1.5; 95% CI, 1.2 to 1.9, after adjustment for actual disease severity). The Kaplan-Meier estimates of mortality were 6.7% with remdesivir and 11.9% with placebo by day 15 and 11.4% with remdesivir and 15.2% with placebo by day 29 (hazard ratio, 0.73; 95% CI, 0.52 to 1.03). Serious adverse events were reported in 131 of the 532 patients who received remdesivir (24.6%) and in 163 of the 516 patients who received placebo (31.6%). CONCLUSIONS: Our data show that remdesivir was superior to placebo in shortening the time to recovery in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection. (Funded by the National Institute of Allergy and Infectious Diseases and others; ACTT-1 ClinicalTrials.gov number, NCT04280705.).
BACKGROUND: Antiretroviral therapy that reduces viral replication could limit the transmission of human immunodeficiency virus type 1 (HIV-1) in serodiscordant couples. METHODS: In nine countries, we enrolled 1763 couples in which one partner was HIV-1-positive and the other was HIV-1-negative; 54% of the subjects were from Africa, and 50% of infected partners were men. HIV-1-infected subjects with CD4 counts between 350 and 550 cells per cubic millimeter were randomly assigned in a 1:1 ratio to receive antiretroviral therapy either immediately (early therapy) or after a decline in the CD4 count or the onset of HIV-1-related symptoms (delayed therapy). The primary prevention end point was linked HIV-1 transmission in HIV-1-negative partners. The primary clinical end point was the earliest occurrence of pulmonary tuberculosis, severe bacterial infection, a World Health Organization stage 4 event, or death. RESULTS: As of February 21, 2011, a total of 39 HIV-1 transmissions were observed (incidence rate, 1.2 per 100 person-years; 95% confidence interval [CI], 0.9 to 1.7); of these, 28 were virologically linked to the infected partner (incidence rate, 0.9 per 100 person-years, 95% CI, 0.6 to 1.3). Of the 28 linked transmissions, only 1 occurred in the early-therapy group (hazard ratio, 0.04; 95% CI, 0.01 to 0.27; P<0.001). Subjects receiving early therapy had fewer treatment end points (hazard ratio, 0.59; 95% CI, 0.40 to 0.88; P=0.01). CONCLUSIONS: The early initiation of antiretroviral therapy reduced rates of sexual transmission of HIV-1 and clinical events, indicating both personal and public health benefits from such therapy. (Funded by the National Institute of Allergy and Infectious Diseases and others; HPTN 052 ClinicalTrials.gov number, NCT00074581.).
DAVID is a popular bioinformatics resource system including a web server and web service for functional annotation and enrichment analyses of gene lists. It consists of a comprehensive knowledgebase and a set of functional analysis tools. Here, we report all updates made in 2021. The DAVID Gene system was rebuilt to gain coverage of more organisms, which increased the taxonomy coverage from 17 399 to 55 464. All existing annotation types have been updated, if available, based on the new DAVID Gene system. Compared with the last version, the number of gene-term records for most annotation types within the updated Knowledgebase have significantly increased. Moreover, we have incorporated new annotations in the Knowledgebase including small molecule-gene interactions from PubChem, drug-gene interactions from DrugBank, tissue expression information from the Human Protein Atlas, disease information from DisGeNET, and pathways from WikiPathways and PathBank. Eight of ten subgroups split from Uniprot Keyword annotation were assigned to specific types. Finally, we added a species parameter for uploading a list of gene symbols to minimize the ambiguity between species, which increases the efficiency of the list upload and eliminates confusion for users. These current updates have significantly expanded the Knowledgebase and enhanced the discovery power of DAVID.
AUTORES: Daniel J Klionsky1745,1749*, Kotb Abdelmohsen840, Akihisa Abe1237, Md Joynal Abedin1762, Hagai Abeliovich425, \nAbraham Acevedo Arozena789, Hiroaki Adachi1800, Christopher M Adams1669, Peter D Adams57, Khosrow Adeli1981, \nPeter J Adhihetty1625, Sharon G Adler700, Galila Agam67, Rajesh Agarwal1587, Manish K Aghi1537, Maria Agnello1826, \nPatrizia Agostinis664, Patricia V Aguilar1960, Julio Aguirre-Ghiso784,786, Edoardo M Airoldi89,422, Slimane Ait-Si-Ali1376, \nTakahiko Akematsu2010, Emmanuel T Akporiaye1097, Mohamed Al-Rubeai1394, Guillermo M Albaiceta1294, \nChris Albanese363, Diego Albani561, Matthew L Albert517, Jesus Aldudo128, Hana Alg€ul1164, Mehrdad Alirezaei1198, \nIraide Alloza642,888, Alexandru Almasan206, Maylin Almonte-Beceril524, Emad S Alnemri1212, Covadonga Alonso544, \nNihal Altan-Bonnet848, Dario C Altieri1205, Silvia Alvarez1497, Lydia Alvarez-Erviti1395, Sandro Alves107, \nGiuseppina Amadoro860, Atsuo Amano930, Consuelo Amantini1554, Santiago Ambrosio1458, Ivano Amelio756, \nAmal O Amer918, Mohamed Amessou2089, Angelika Amon726, Zhenyi An1538, Frank A Anania291, Stig U Andersen6, \nUsha P Andley2079, Catherine K Andreadi1690, Nathalie Andrieu-Abadie502, Alberto Anel2027, David K Ann58, \nShailendra Anoopkumar-Dukie388, Manuela Antonioli832,858, Hiroshi Aoki1791, Nadezda Apostolova2007, \nSaveria Aquila1500, Katia Aquilano1876, Koichi Araki292, Eli Arama2098, Agustin Aranda456, Jun Araya591, \nAlexandre Arcaro1472, Esperanza Arias26, Hirokazu Arimoto1225, Aileen R Ariosa1749, Jane L Armstrong1930, \nThierry Arnould1773, Ivica Arsov2120, Katsuhiko Asanuma675, Valerie Askanas1924, Eric Asselin1867, Ryuichiro Atarashi794, \nSally S Atherton369, Julie D Atkin713, Laura D Attardi1131, Patrick Auberger1787, Georg Auburger379, Laure Aurelian1727, \nRiccardo Autelli1992, Laura Avagliano1029,1755, Maria Laura Avantaggiati364, Limor Avrahami1166, Suresh Awale1986, \nNeelam Azad404, Tiziana Bachetti568, Jonathan M Backer28, Dong-Hun Bae1933, Jae-sung Bae677, Ok-Nam Bae409, \nSoo Han Bae2117, Eric H Baehrecke1729, Seung-Hoon Baek17, Stephen Baghdiguian1368, \nAgnieszka Bagniewska-Zadworna2, Hua Bai90, Jie Bai667, Xue-Yuan Bai1133, Yannick Bailly884, \nKithiganahalli Narayanaswamy Balaji473, Walter Balduini2002, Andrea Ballabio316, Rena Balzan1711, Rajkumar Banerjee239, \nG abor B anhegyi1052, Haijun Bao2109, Benoit Barbeau1363, Maria D Barrachina2007, Esther Barreiro467, Bonnie Bartel997, \nAlberto Bartolom e222, Diane C Bassham550, Maria Teresa Bassi1046, Robert C Bast Jr1273, Alakananda Basu1798, \nMaria Teresa Batista1578, Henri Batoko1336, Maurizio Battino970, Kyle Bauckman2085, Bradley L Baumgarner1909, \nK Ulrich Bayer1594, Rupert Beale1553, Jean-Fran¸cois Beaulieu1360, George R. Beck Jr48,294, Christoph Becker336, \nJ David Beckham1595, Pierre-Andr e B edard749, Patrick J Bednarski301, Thomas J Begley1135, Christian Behl1419, \nChristian Behrends757, Georg MN Behrens406, Kevin E Behrns1627, Eloy Bejarano26, Amine Belaid490, \nFrancesca Belleudi1041, Giovanni B enard497, Guy Berchem706, Daniele Bergamaschi983, Matteo Bergami1401, \nBen Berkhout1441, Laura Berliocchi714, Am elie Bernard1749, Monique Bernard1354, Francesca Bernassola1880, \nAnne Bertolotti791, Amanda S Bess272, S ebastien Besteiro1351, Saverio Bettuzzi1828, Savita Bhalla913, \nShalmoli Bhattacharyya973, Sujit K Bhutia838, Caroline Biagosch1159, Michele Wolfe Bianchi520,1378,1381, \nMartine Biard-Piechaczyk210, Viktor Billes298, Claudia Bincoletto1314, Baris Bingol350, Sara W Bird1128, Marc Bitoun1112, \nIvana Bjedov1258, Craig Blackstone843, Lionel Blanc1183, Guillermo A Blanco1496, Heidi Kiil Blomhoff1812, \nEmilio Boada-Romero1297, Stefan B€ockler1464, Marianne Boes1423, Kathleen Boesze-Battaglia1835, Lawrence H Boise286,287, \nAlessandra Bolino2063, Andrea Boman693, Paolo Bonaldo1823, Matteo Bordi897, J€urgen Bosch608, Luis M Botana1308, \nJoelle Botti1375, German Bou1405, Marina Bouch e1038, Marion Bouchecareilh1331, Marie-Jos ee Boucher1901, \nMichael E Boulton481, Sebastien G Bouret1926, Patricia Boya133, Micha€el Boyer-Guittaut1345, Peter V Bozhkov1141, \nNathan Brady374, Vania MM Braga469, Claudio Brancolini1997, Gerhard H Braus353, Jos e M Bravo-San Pedro299,393,508,1374, \nLisa A Brennan322, Emery H Bresnick2022, Patrick Brest490, Dave Bridges1939, Marie-Agn es Bringer124, Marisa Brini1822, \nGlauber C Brito1311, Bertha Brodin631, Paul S Brookes1872, Eric J Brown352, Karen Brown1690, Hal E Broxmeyer480, \nAlain Bruhat486,1339, Patricia Chakur Brum1893, John H Brumell446, Nicola Brunetti-Pierri315,1171, \nRobert J Bryson-Richardson781, Shilpa Buch1777, Alastair M Buchan1819, Hikmet Budak1022, Dmitry V Bulavin118,505,1789, \nScott J Bultman1792, Geert Bultynck665, Vladimir Bumbasirevic1470, Yan Burelle1356, Robert E Burke216,217, \nMargit Burmeister1750, Peter B€utikofer1473, Laura Caberlotto1987, Ken Cadwell896, Monika Cahova112, Dongsheng Cai24, \nJingjing Cai2099, Qian Cai1018, Sara Calatayud2007, Nadine Camougrand1343, Michelangelo Campanella1700, \nGrant R Campbell1525, Matthew Campbell1249, Silvia Campello556,1876, Robin Candau1769, Isabella Caniggia1983, \nLavinia Cantoni560, Lizhi Cao116, Allan B Caplan1656, Michele Caraglia1051, Claudio Cardinali1043, Sandra Morais Cardoso1579, Jennifer S Carew208, Laura A Carleton874, Cathleen R Carlin101, Silvia Carloni2002, \nSven R Carlsson1267, Didac Carmona-Gutierrez1643, Leticia AM Carneiro312, Oliana Carnevali971, Serena Carra1318, \nAlice Carrier120, Bernadette Carroll900, Caty Casas1324, Josefina Casas1116, Giuliana Cassinelli324, Perrine Castets1462, \nSusana Castro-Obregon214, Gabriella Cavallini1841, Isabella Ceccherini568, Francesco Cecconi253,555,1884, \nArthur I Cederbaum459, Valent ın Ce~na199,1281, Simone Cenci1323,2064, Claudia Cerella444, Davide Cervia1996, \nSilvia Cetrullo1478, Hassan Chaachouay2028, Han-Jung Chae187, Andrei S Chagin634, Chee-Yin Chai626,628, \nGopal Chakrabarti1502, Georgios Chamilos1601, Edmond YW Chan1142, Matthew TV Chan181, Dhyan Chandra1003, \nPallavi Chandra548, Chih-Peng Chang818, Raymond Chuen-Chung Chang1653, Ta Yuan Chang345, John C Chatham1434, \nSaurabh Chatterjee1910, Santosh Chauhan527, Yongsheng Che62, Michael E Cheetham1263, Rajkumar Cheluvappa1783, \nChun-Jung Chen1153, Gang Chen598,1676, Guang-Chao Chen9, Guoqiang Chen1078, Hongzhuan Chen1077, Jeff W Chen1514, \nJian-Kang Chen370,371, Min Chen249, Mingzhou Chen2104, Peiwen Chen1823, Qi Chen1674, Quan Chen172, \nShang-Der Chen138, Si Chen325, Steve S-L Chen10, Wei Chen2125, Wei-Jung Chen829, Wen Qiang Chen979, Wenli Chen1113, \nXiangmei Chen1133, Yau-Hung Chen1157, Ye-Guang Chen1250, Yin Chen1447, Yingyu Chen953,955, Yongshun Chen2135, \nYu-Jen Chen712, Yue-Qin Chen1145, Yujie Chen1208, Zhen Chen339, Zhong Chen2123, Alan Cheng1702, \nChristopher HK Cheng184, Hua Cheng1728, Heesun Cheong814, Sara Cherry1836, Jason Chesney1703, \nChun Hei Antonio Cheung817, Eric Chevet1359, Hsiang Cheng Chi140, Sung-Gil Chi656, Fulvio Chiacchiera308, \nHui-Ling Chiang958, Roberto Chiarelli1826, Mario Chiariello235,567,577, Marcello Chieppa835, Lih-Shen Chin290, \nMario Chiong1285, Gigi NC Chiu878, Dong-Hyung Cho676, Ssang-Goo Cho650, William C Cho982, Yong-Yeon Cho105, \nYoung-Seok Cho1064, Augustine MK Choi2095, Eui-Ju Choi656, Eun-Kyoung Choi387,400,685, Jayoung Choi1563, \nMary E Choi2093, Seung-Il Choi2116, Tsui-Fen Chou412, Salem Chouaib395, Divaker Choubey1574, Vinay Choubey1936, \nKuan-Chih Chow822, Kamal Chowdhury730, Charleen T Chu1856, Tsung-Hsien Chuang827, Taehoon Chun657, \nHyewon Chung652, Taijoon Chung978, Yuen-Li Chung1194, Yong-Joon Chwae18, Valentina Cianfanelli254, \nRoberto Ciarcia1775, Iwona A Ciechomska886, Maria Rosa Ciriolo1876, Mara Cirone1042, Sofie Claerhout1694, \nMichael J Clague1698, Joan Cl aria1457, Peter GH Clarke1687, Robert Clarke361, Emilio Clementi1045,1398, C edric Cleyrat1781, \nMiriam Cnop1366, Eliana M Coccia574, Tiziana Cocco1459, Patrice Codogno1375, J€orn Coers271, Ezra EW Cohen1533, \nDavid Colecchia235,567,577, Luisa Coletto25, N uria S Coll123, Emma Colucci-Guyon516, Sergio Comincini1829, \nMaria Condello578, Katherine L Cook2073, Graham H Coombs1929, Cynthia D Cooper2076, J Mark Cooper1395, \nIsabelle Coppens601, Maria Tiziana Corasaniti1387, Marco Corazzari485,1884, Ramon Corbalan1566, \nElisabeth Corcelle-Termeau251, Mario D Cordero1899, Cristina Corral-Ramos1289, Olga Corti507,1109, Andrea Cossarizza1767, \nPaola Costelli1993, Safia Costes1518, Susan L Cotman721, Ana Coto-Montes946, Sandra Cottet566,1688, Eduardo Couve1301, \nLori R Covey1015, L Ashley Cowart762, Jeffery S Cox1536, Fraser P Coxon1427, Carolyn B Coyne1846, Mark S Cragg1919, \nRolf J Craven1679, Tiziana Crepaldi1995, Jose L Crespo1300, Alfredo Criollo1285, Valeria Crippa558, Maria Teresa Cruz1576, \nAna Maria Cuervo26, Jose M Cuezva1277, Taixing Cui1907, Pedro R Cutillas987, Mark J Czaja27, Maria F Czyzyk-Krzeska1572, \nRuben K Dagda2068, Uta Dahmen1404, Chunsun Dai800, Wenjie Dai1187, Yun Dai2059, Kevin N Dalby1940, \nLuisa Dalla Valle1822, Guillaume Dalmasso1340, Marcello D’Amelio557, Markus Damme188, Arlette Darfeuille-Michaud1340, \nCatherine Dargemont950, Victor M Darley-Usmar1433, Srinivasan Dasarathy205, Biplab Dasgupta202, Srikanta Dash1254, \nCrispin R Dass242, Hazel Marie Davey8, Lester M Davids1560, David D avila227, Roger J Davis1731, Ted M Dawson604, \nValina L Dawson606, Paula Daza1898, Jackie de Belleroche470, Paul de Figueiredo1180,1182, \nRegina Celia Bressan Queiroz de Figueiredo135, Jos e de la Fuente1023, Luisa De Martino1775, \nAntonella De Matteis1171, Guido RY De Meyer1443, Angelo De Milito631, Mauro De Santi2002,
BACKGROUND: Antiretroviral chemoprophylaxis before exposure is a promising approach for the prevention of human immunodeficiency virus (HIV) acquisition. METHODS: We randomly assigned 2499 HIV-seronegative men or transgender women who have sex with men to receive a combination of two oral antiretroviral drugs, emtricitabine and tenofovir disoproxil fumarate (FTC-TDF), or placebo once daily. All subjects received HIV testing, risk-reduction counseling, condoms, and management of sexually transmitted infections. RESULTS: The study subjects were followed for 3324 person-years (median, 1.2 years; maximum, 2.8 years). Of these subjects, 10 were found to have been infected with HIV at enrollment, and 100 became infected during follow-up (36 in the FTC-TDF group and 64 in the placebo group), indicating a 44% reduction in the incidence of HIV (95% confidence interval, 15 to 63; P=0.005). In the FTC-TDF group, the study drug was detected in 22 of 43 of seronegative subjects (51%) and in 3 of 34 HIV-infected subjects (9%) (P<0.001). Nausea was reported more frequently during the first 4 weeks in the FTC-TDF group than in the placebo group (P<0.001). The two groups had similar rates of serious adverse events (P=0.57). CONCLUSIONS: Oral FTC-TDF provided protection against the acquisition of HIV infection among the subjects. Detectable blood levels strongly correlated with the prophylactic effect. (Funded by the National Institutes of Health and the Bill and Melinda Gates Foundation; ClinicalTrials.gov number, NCT00458393.).
For many years immunologists have been well served by the viewpoint that the immune system's primary goal is to discriminate between self and non-self. I believe that it is time to change viewpoints and, in this essay, I discuss the possibility that the immune system does not care about self and non-self, that its primary driving force is the need to detect and protect against danger, and that it does not do the job alone, but receives positive and negative communications from an extended network of other bodily tissues.
Allergic rhinitis is a symptomatic disorder of the nose\ninduced after allergen exposure by an IgE-mediated\ninflammation of the membranes lining the nose. It is a\nglobal health problem that causes major illness and disability\nworldwide. Over 600 million patients from all\ncountries, all ethnic groups and of all ages suffer from\nallergic rhinitis. It affects social life, sleep, school and\nwork and its economic impact is substantial.\nRisk factors for allergic rhinitis are well identified.\nIndoor and outdoor allergens as well as occupational\nagents cause rhinitis and other allergic diseases.\nThe role of indoor and outdoor pollution is probably\nvery important, but has yet to be fully understood\nboth for the occurrence of the disease and its manifestations.\nIn 1999, during the Allergic Rhinitis and its Impact on\nAsthma (ARIA) WHO workshop, the expert panel\nproposed a new classification for allergic rhinitis which\nwas subdivided into _intermittent_ or _persistent_ disease.\nThis classification is now validated.\nThe diagnosis of allergic rhinitis is often quite easy, but\nin some cases it may cause problems and many patients\nare still under-diagnosed, often because they do not\nperceive the symptoms of rhinitis as a disease impairing\ntheir social life, school and work.\nThe management of allergic rhinitis is well established\nand the ARIA expert panel based its recommendations\non evidence using an extensive review of the literature\navailable up to December 1999. The statements of\nevidence for the development of these guidelines followed\nWHO rules and were based on those of Shekelle et al.\nA large number of papers have been published since 2000\nand are extensively reviewed in the 2008 Update using\nthe same evidence-based system. Recommendations for\nthe management of allergic rhinitis are similar in both the\nARIA workshop report and the 2008 Update. In the\nfuture, the GRADE approach will be used, but is not yet\navailable.\nAnother important aspect of the ARIA guidelines was\nto consider co-morbidities. Both allergic rhinitis and\nasthma are systemic inflammatory conditions and often\nco-exist in the same patients. In the 2008 Update, these\nlinks have been confirmed.\nTheARIAdocument is not intended to be a standard-ofcare\ndocument for individual countries. It is provided as a\nbasis for physicians, health care professionals and\norganizations involved in the treatment of allergic rhinitis\nand asthma in various countries to facilitate the\ndevelopment of relevant local standard-of-care documents\nfor patients.
Characterization of the molecular function of the human genome and its variation across individuals is essential for identifying the cellular mechanisms that underlie human genetic traits and diseases. The Genotype-Tissue Expression (GTEx) project aims to characterize variation in gene expression levels across individuals and diverse tissues of the human body, many of which are not easily accessible. Here we describe genetic effects on gene expression levels across 44 human tissues. We find that local genetic variation affects gene expression levels for the majority of genes, and we further identify inter-chromosomal genetic effects for 93 genes and 112 loci. On the basis of the identified genetic effects, we characterize patterns of tissue specificity, compare local and distal effects, and evaluate the functional properties of the genetic effects. We also demonstrate that multi-tissue, multi-individual data can be used to identify genes and pathways affected by human disease-associated variation, enabling a mechanistic interpretation of gene regulation and the genetic basis of disease.
Fibrosis is defined by the overgrowth, hardening, and/or scarring of various tissues and is attributed to excess deposition of extracellular matrix components including collagen. Fibrosis is the end result of chronic inflammatory reactions induced by a variety of stimuli including persistent infections, autoimmune reactions, allergic responses, chemical insults, radiation, and tissue injury. Although current treatments for fibrotic diseases such as idiopathic pulmonary fibrosis, liver cirrhosis, systemic sclerosis, progressive kidney disease, and cardiovascular fibrosis typically target the inflammatory response, there is accumulating evidence that the mechanisms driving fibrogenesis are distinct from those regulating inflammation. In fact, some studies have suggested that ongoing inflammation is needed to reverse established and progressive fibrosis. The key cellular mediator of fibrosis is the myofibroblast, which when activated serves as the primary collagen-producing cell. Myofibroblasts are generated from a variety of sources including resident mesenchymal cells, epithelial and endothelial cells in processes termed epithelial/endothelial-mesenchymal (EMT/EndMT) transition, as well as from circulating fibroblast-like cells called fibrocytes that are derived from bone-marrow stem cells. Myofibroblasts are activated by a variety of mechanisms, including paracrine signals derived from lymphocytes and macrophages, autocrine factors secreted by myofibroblasts, and pathogen-associated molecular patterns (PAMPS) produced by pathogenic organisms that interact with pattern recognition receptors (i.e. TLRs) on fibroblasts. Cytokines (IL-13, IL-21, TGF-beta1), chemokines (MCP-1, MIP-1beta), angiogenic factors (VEGF), growth factors (PDGF), peroxisome proliferator-activated receptors (PPARs), acute phase proteins (SAP), caspases, and components of the renin-angiotensin-aldosterone system (ANG II) have been identified as important regulators of fibrosis and are being investigated as potential targets of antifibrotic drugs. This review explores our current understanding of the cellular and molecular mechanisms of fibrogenesis.
For over 50 years immunologists have based their thoughts, experiments, and clinical treatments on the idea that the immune system functions by making a distinction between self and nonself. Although this paradigm has often served us well, years of detailed examination have revealed a number of inherent problems. This Viewpoint outlines a model of immunity based on the idea that the immune system is more concerned with entities that do damage than with those that are foreign.
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BACKGROUND AND METHODS: Maternal-infant transmission is the primary means by which young children become infected with human immunodeficiency virus type 1 (HIV). We conducted a randomized, double-blind, placebo-controlled trial of the efficacy and safety of zidovudine in reducing the risk of maternal-infant HIV transmission. HIV-infected pregnant women (14 to 34 weeks' gestation) with CD4+ T-lymphocyte counts above 200 cells per cubic millimeter who had not received antiretroviral therapy during the current pregnancy were enrolled. The zidovudine regimen included antepartum zidovudine (100 mg orally five times daily), intrapartum zidovudine (2 mg per kilogram of body weight given intravenously over one hour, then 1 mg per kilogram per hour until delivery), and zidovudine for the newborn (2 mg per kilogram orally every six hours for six weeks). Infants with at least one positive HIV culture of peripheral-blood mononuclear cells were classified as HIV-infected. RESULTS: From April 1991 through December 20, 1993, the cutoff date for the first interim analysis of efficacy, 477 pregnant women were enrolled; during the study period, 409 gave birth to 415 live-born infants. HIV-infection status was known for 363 births (180 in the zidovudine group and 183 in the placebo group). Thirteen infants in the zidovudine group and 40 in the placebo group were HIV-infected. The proportions infected at 18 months, as estimated by the Kaplan-Meier method, were 8.3 percent (95 percent confidence interval, 3.9 to 12.8 percent) in the zidovudine group and 25.5 percent (95 percent confidence interval, 18.4 to 32.5 percent) in the placebo group. This corresponds to a 67.5 percent (95 percent confidence interval, 40.7 to 82.1 percent) relative reduction in the risk of HIV transmission (Z = 4.03, P = 0.00006). Minimal short-term toxic effects were observed. The level of hemoglobin at birth in the infants in the zidovudine group was significantly lower than that in the infants in the placebo group. By 12 weeks of age, hemoglobin values in the two groups were similar. CONCLUSIONS: In pregnant women with mildly symptomatic HIV disease and no prior treatment with antiretroviral drugs during the pregnancy, a regimen consisting of zidovudine given ante partum and intra partum to the mother and to the newborn for six weeks reduced the risk of maternal-infant HIV transmission by approximately two thirds.
We have previously shown correction of X-linked severe combined immunodeficiency [SCID-X1, also known as gamma chain (gamma(c)) deficiency] in 9 out of 10 patients by retrovirus-mediated gamma(c) gene transfer into autologous CD34 bone marrow cells. However, almost 3 years after gene therapy, uncontrolled exponential clonal proliferation of mature T cells (with gammadelta+ or alphabeta+ T cell receptors) has occurred in the two youngest patients. Both patients' clones showed retrovirus vector integration in proximity to the LMO2 proto-oncogene promoter, leading to aberrant transcription and expression of LMO2. Thus, retrovirus vector insertion can trigger deregulated premalignant cell proliferation with unexpected frequency, most likely driven by retrovirus enhancer activity on the LMO2 gene promoter.
CD4 T cells play critical roles in mediating adaptive immunity to a variety of pathogens. They are also involved in autoimmunity, asthma, and allergic responses as well as in tumor immunity. During TCR activation in a particular cytokine milieu, naive CD4 T cells may differentiate into one of several lineages of T helper (Th) cells, including Th1, Th2, Th17, and iTreg, as defined by their pattern of cytokine production and function. In this review, we summarize the discovery, functions, and relationships among Th cells; the cytokine and signaling requirements for their development; the networks of transcription factors involved in their differentiation; the epigenetic regulation of their key cytokines and transcription factors; and human diseases involving defective CD4 T cell differentiation.
A specific assay has been developed for a blood-borne non-A, non-B hepatitis (NANBH) virus in which a polypeptide synthesized in recombinant yeast clones of the hepatitis C virus (HCV) is used to capture circulating viral antibodies. HCV antibodies were detected in six of seven human sera that were shown previously to transmit NANBH to chimpanzees. Assays of ten blood transfusions in the United States that resulted in chronic NANBH revealed that there was at least one positive blood donor in nine of these cases and that all ten recipients seroconverted during their illnesses. About 80 percent of chronic, post-transfusion NANBH (PT-NANBH) patients from Italy and Japan had circulating HCV antibody; a much lower frequency (15 percent) was observed in acute, resolving infections. In addition, 58 percent of NANBH patients from the United States with no identifiable source of parenteral exposure to the virus were also positive for HCV antibody. These data indicate that HCV is a major cause of NANBH throughout the world.